{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T10:28:05Z","timestamp":1789122485019,"version":"build-2803163510"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,30]],"date-time":"2022-05-30T00:00:00Z","timestamp":1653868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Under steady-state conditions, conventional CD4<jats:sup>+<\/jats:sup>T lymphocytes are classically divided into na\u00efve (CD44<jats:sup>lo<\/jats:sup>CD62L<jats:sup>hi<\/jats:sup>) and memory (CD44<jats:sup>hi<\/jats:sup>CD62L<jats:sup>lo<\/jats:sup>) cell compartments. While the latter population is presumed to comprise a mixture of distinct subpopulations of explicit foreign antigen (Ag)-specific \u201cauthentic\u201d memory and foreign Ag-independent memory-phenotype (MP) cells, phenotypic markers differentially expressed in these two cell types have yet to be identified. Moreover, while MP cells themselves have been previously described as heterogeneous, it is unknown whether they consist of distinct subsets defined by marker expression. In this study, we demonstrate using combined single-cell RNA sequencing and flow cytometric approaches that self-driven MP CD4<jats:sup>+<\/jats:sup>T lymphocytes are divided into CD127<jats:sup>hi<\/jats:sup>Sca1<jats:sup>lo<\/jats:sup>, CD127<jats:sup>hi<\/jats:sup>Sca1<jats:sup>hi<\/jats:sup>, CD127<jats:sup>lo<\/jats:sup>Sca1<jats:sup>hi<\/jats:sup>, and CD127<jats:sup>lo<\/jats:sup>Sca1<jats:sup>lo<\/jats:sup>subpopulations that are Bcl2<jats:sup>lo<\/jats:sup>, while foreign Ag-specific memory cells are CD127<jats:sup>hi<\/jats:sup>Sca1<jats:sup>hi<\/jats:sup>Bcl2<jats:sup>hi<\/jats:sup>. We further show that among the four MP subsets, CD127<jats:sup>hi<\/jats:sup>Sca1<jats:sup>hi<\/jats:sup>lymphocytes represent the most mature and cell division-experienced subpopulation derived from peripheral na\u00efve precursors. Finally, we provide evidence arguing that this MP subpopulation exerts the highest responsiveness to Th1-differentiating cytokines and can induce colitis. Together, our findings define MP CD4<jats:sup>+<\/jats:sup>T lymphocytes as a unique, self-driven population consisting of distinct subsets that differ from conventional foreign Ag-specific memory cells in marker expression and establish functional relevance for the mature subset of CD127<jats:sup>hi<\/jats:sup>Sca1<jats:sup>hi<\/jats:sup>MP cells.<\/jats:p>","DOI":"10.3389\/fimmu.2022.870542","type":"journal-article","created":{"date-parts":[[2022,5,30]],"date-time":"2022-05-30T13:33:55Z","timestamp":1653917635000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["Redefining the Foreign Antigen and Self-Driven Memory CD4+ T-Cell Compartments via Transcriptomic, Phenotypic, and Functional Analyses"],"prefix":"10.3389","volume":"13","author":[{"given":"Takeshi","family":"Kawabe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Ciucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwang Soon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunichi","family":"Tayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihisa","family":"Kawajiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takumi","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riou","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Ishii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragana","family":"Jankovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfang","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Sprent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00e9my","family":"Bosselut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Sher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2018","article-title":"Normal T Cell Homeostasis: The Conversion of Naive Cells Into Memory-Phenotype Cells","volume":"12","author":"Sprent","year":"2011","journal-title":"Nat Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a037879","article-title":"Homeostasis of Naive and Memory T Lymphocytes","volume":"13","author":"Kawabe","year":"2021","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxab108","article-title":"Memory-Phenotype Cd4 + T Cells: A Naturally Arising T Lymphocyte Population Possessing Innate Immune Function","volume":"34","author":"Kawabe","year":"2022","journal-title":"Int Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aam9304","article-title":"Memory-Phenotype Cd4(+) T Cells Spontaneously Generated Under Steady-State Conditions Exert Innate Th1-Like Effector Function","volume":"2","author":"Kawabe","year":"2017","journal-title":"Sci Immunol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"3366","DOI":"10.1038\/s41467-020-17136-1","article-title":"Requirements for the Differentiation of Innate T-Bet(High) Memory-Phenotype Cd4(+) T Lymphocytes Under Steady State","volume":"11","author":"Kawabe","year":"2020","journal-title":"Nat Commun"},{"key":"B6","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/nature14189","article-title":"The Biology of Innate Lymphoid Cells","volume":"517","author":"Artis","year":"2015","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1038\/nri.2017.34","article-title":"Antigen-Inexperienced Memory CD8(+) T Cells: Where They Come From and Why We Need Them","volume":"17","author":"White","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2018.12","article-title":"Foreign Antigen-Independent Memory-Phenotype CD4(+) T Cells: A New Player in Innate Immunity","volume":"18","author":"Kawabe","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1146\/annurev.immunol.25.022106.141711","article-title":"The Biology of Nkt Cells","volume":"25","author":"Bendelac","year":"2007","journal-title":"Annu Rev Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0444-8","article-title":"The Biology and Functional Importance of Mait Cells","volume":"20","author":"Godfrey","year":"2019","journal-title":"Nat Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20020066","article-title":"Interleukin (IL)-15 and IL-7 Jointly Regulate Homeostatic Proliferation of Memory Phenotype Cd8+ Cells But Are Not Required for Memory Phenotype Cd4+ Cells","volume":"195","author":"Tan","year":"2002","journal-title":"J Exp Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20061805","article-title":"Antiviral CD4+ Memory T Cells Are Il-15 Dependent","volume":"204","author":"Purton","year":"2007","journal-title":"J Exp Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201444701","article-title":"Ox40 and Il-7 Play Synergistic Roles in the Homeostatic Proliferation of Effector Memory Cd4(+) T Cells","volume":"44","author":"Yamaki","year":"2014","journal-title":"Eur J Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030735","article-title":"Interleukin 7 Regulates the Survival and Generation of Memory CD4 Cells","volume":"198","author":"Kondrack","year":"2003","journal-title":"J Exp Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0400640101","article-title":"Il-7 Regulates Basal Homeostatic Proliferation of Antiviral Cd4+T Cell Memory","volume":"101","author":"Lenz","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/s1074-7613(00)80092-8","article-title":"The Peptide Ligands Mediating Positive Selection in the Thymus Control T Cell Survival and Homeostatic Proliferation in the Periphery","volume":"11","author":"Ernst","year":"1999","journal-title":"Immunity"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/s1074-7613(00)80055-2","article-title":"Designing and Maintaining the Mature Tcr Repertoire: The Continuum of Self-Peptide:Self-Mhc Complex Recognition","volume":"10","author":"Viret","year":"1999","journal-title":"Immunity"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.6.3158","article-title":"Recent Immune Status Determines the Source of Antigens That Drive Homeostatic T Cell Expansion","volume":"174","author":"Kieper","year":"2005","journal-title":"J Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.10.6039","article-title":"Spontaneous and Homeostatic Proliferation of Cd4 T Cells Are Regulated by Different Mechanisms","volume":"174","author":"Min","year":"2005","journal-title":"J Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1203111","article-title":"Homeostatic Proliferation of Naive CD4+ T Cells in Mesenteric Lymph Nodes Generates Gut-Tropic Th17 Cells","volume":"190","author":"Kawabe","year":"2013","journal-title":"J Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/s1074-7613(00)00045-5","article-title":"Cd40 Triggering of Heterodimeric IL-12 P70 Production by Dendritic Cells in Vivo Requires a Microbial Priming Signal","volume":"13","author":"Schulz","year":"2000","journal-title":"Immunity"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001171","article-title":"Memory Phenotype CD4 T Cells Undergoing Rapid, Nonburst-Like, Cytokine-Driven Proliferation Can Be Distinguished From Antigen-Experienced Memory Cells","volume":"9","author":"Younes","year":"2011","journal-title":"PloS Biol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1084\/jem.179.4.1127","article-title":"Turnover of Naive- and Memory-Phenotype T Cells","volume":"179","author":"Tough","year":"1994","journal-title":"J Exp Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nature07486","article-title":"Memory Cd8 T-Cell Compartment Grows in Size With Immunological Experience","volume":"457","author":"Vezys","year":"2009","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/nature17655","article-title":"Normalizing the Environment Recapitulates Adult Human Immune Traits in Laboratory Mice","volume":"532","author":"Beura","year":"2016","journal-title":"Nature"},{"key":"B26","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/nrc.2016.138","article-title":"Cell Cycle Proteins as Promising Targets in Cancer Therapy","volume":"17","author":"Otto","year":"2017","journal-title":"Nat Rev Cancer"},{"key":"B27","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.immuni.2018.12.019","article-title":"The Emergence and Functional Fitness of Memory CD4(+) T Cells Require the Transcription Factor Thpok","volume":"50","author":"Ciucci","year":"2019","journal-title":"Immunity"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(02)01139-x","article-title":"Molecular and Functional Profiling of Memory CD8 T Cell Differentiation","volume":"111","author":"Kaech","year":"2002","journal-title":"Cell"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nm1326","article-title":"Host-Reactive CD8+ Memory Stem Cells in Graft-Versus-Host Disease","volume":"11","author":"Zhang","year":"2005","journal-title":"Nat Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1701154","article-title":"Cytokine- and Tcr-Mediated Regulation of T Cell Expression of Ly6c and Sca-1","volume":"200","author":"DeLong","year":"2018","journal-title":"J Immunol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1111\/j.1365-2141.2008.07562.x","article-title":"Gene Expression of Anti- and Pro-Apoptotic Proteins in Malignant and Normal Plasma Cells","volume":"145","author":"Jourdan","year":"2009","journal-title":"Br J Haematol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(00)80291-3","article-title":"Bcl-2 Rescues T Lymphopoiesis in Interleukin-7 Receptor-Deficient Mice","volume":"89","author":"Akashi","year":"1997","journal-title":"Cell"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1126\/science.aac5560","article-title":"Dietary Antigens Limit Mucosal Immunity by Inducing Regulatory T Cells in the Small Intestine","volume":"351","author":"Kim","year":"2016","journal-title":"Science"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1898","article-title":"T Cells Expressing the Transcription Factor Plzf Regulate the Development of Memory-Like CD8+ T Cells","volume":"11","author":"Weinreich","year":"2010","journal-title":"Nat Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.09.011","article-title":"T Cell-Positive Selection Uses Self-Ligand Binding Strength to Optimize Repertoire Recognition of Foreign Antigens","volume":"38","author":"Mandl","year":"2013","journal-title":"Immunity"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110308","article-title":"T Cell Receptor Signal Strength in Treg and Inkt Cell Development Demonstrated by a Novel Fluorescent Reporter Mouse","volume":"208","author":"Moran","year":"2011","journal-title":"J Exp Med"},{"key":"B37","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.152.10.4919","article-title":"Second Signal Activity of Il-12 on the Proliferation and IL-2r Expression of T Helper Cell-1 Clone","volume":"152","author":"Yanagida","year":"1994","journal-title":"J Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-4141(200005)30:5<1445::AID-IMMU1445>3.0.CO;2-M","article-title":"IL-12 Enhances IL-2 Function by Inducing CD25 Expression Through a P38 Mitogen-Activated Protein Kinase Pathway","volume":"30","author":"Nguyen","year":"2000","journal-title":"Eur J Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900960","article-title":"The Colon as a Major Site of Immunoregulation by CD4(+) T Cell Subsets in the Steady State","volume":"203","author":"Sher","year":"2019","journal-title":"J Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/5.11.1461","article-title":"Phenotypically Distinct Subsets of CD4+ T Cells Induce or Protect From Chronic Intestinal Inflammation in C. B-17 Scid Mice","volume":"5","author":"Powrie","year":"1993","journal-title":"Int Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20081829","article-title":"The Antigen-Specific CD8+ T Cell Repertoire in Unimmunized Mice Includes Memory Phenotype Cells Bearing Markers of Homeostatic Expansion","volume":"206","author":"Haluszczak","year":"2009","journal-title":"J Exp Med"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1701698","article-title":"Antigen-Induced But Not Innate Memory CD8 T Cells Express Nkg2d and Are Recruited to the Lung Parenchyma Upon Viral Infection","volume":"200","author":"Grau","year":"2018","journal-title":"J Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1307572110","article-title":"Virtual Memory CD8 T Cells Display Unique Functional Properties","volume":"110","author":"Lee","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"B44","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.immuni.2017.07.005","article-title":"Interleukin-7 Availability Is Maintained by a Hematopoietic Cytokine Sink Comprising Innate Lymphoid Cells and T Cells","volume":"47","author":"Martin","year":"2017","journal-title":"Immunity"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1922525117","article-title":"CD5 Dynamically Calibrates Basal Nf-Kappab Signaling in T Cells During Thymic Development and Peripheral Activation","volume":"117","author":"Matson","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.08.008","article-title":"Subsets of Nonclonal Neighboring Cd4+ T Cells Specifically Regulate the Frequency of Individual Antigen-Reactive T Cells","volume":"37","author":"Singh","year":"2012","journal-title":"Immunity"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/ni1428","article-title":"Regulatory T Cells Prevent Catastrophic Autoimmunity Throughout the Lifespan of Mice","volume":"8","author":"Kim","year":"2007","journal-title":"Nat Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1818624116","article-title":"Unregulated Antigen-Presenting Cell Activation by T Cells Breaks Self Tolerance","volume":"116","author":"Yi","year":"2019","journal-title":"Proc Natl Acad Sci USA"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1126\/science.7542801","article-title":"A Role for CD5 in Tcr-Mediated Signal Transduction and Thymocyte Selection","volume":"269","author":"Tarakhovsky","year":"1995","journal-title":"Science"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20082553","article-title":"Self-Class I Mhc Molecules Support Survival of Naive CD8 T Cells, But Depress Their Functional Sensitivity Through Regulation of CD8 Expression Levels","volume":"206","author":"Takada","year":"2009","journal-title":"J Exp Med"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13373","article-title":"CD45-Mediated Control of TCR Tuning in Naive and Memory CD8(+) T Cells","volume":"7","author":"Cho","year":"2016","journal-title":"Nat Commun"},{"key":"B52","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.152.6.3098","article-title":"A Novel Subpopulation of Primed T Cells in the Human Fetus","volume":"152","author":"Byrne","year":"1994","journal-title":"J Immunol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/s0301-472x(03)00160-7","article-title":"Coexistent Naive Phenotype and Higher Cycling Rate of Cord Blood T Cells as Compared to Adult Peripheral Blood","volume":"31","author":"Szabolcs","year":"2003","journal-title":"Exp Hematol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2425-3","article-title":"The Liver-Brain-Gut Neural Arc Maintains the Treg Cell Niche in the Gut","volume":"585","author":"Teratani","year":"2020","journal-title":"Nature"},{"key":"B55","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1093\/ecco-jcc\/jjy035","article-title":"Development of Reliable, Valid and Responsive Scoring Systems for Endoscopy and Histology in Animal Models for Inflammatory Bowel Disease","volume":"12","author":"Koelink","year":"2018","journal-title":"J Crohns Colitis"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14049","article-title":"Massively Parallel Digital Transcriptional Profiling of Single Cells","volume":"8","author":"Zheng","year":"2017","journal-title":"Nat Commun"},{"key":"B57","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive Integration of Single-Cell Data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1701186","article-title":"IL-4 and IL-13 Guide Early Thymic Progenitors to Mature Toward Dendritic Cells","volume":"201","author":"Barik","year":"2018","journal-title":"J Immunol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.252464599","article-title":"Nitric Oxide Preferentially Induces Type 1 T Cell Differentiation by Selectively Up-Regulating Il-12 Receptor Beta 2 Expression Via Cgmp","volume":"99","author":"Niedbala","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2019.04.026","article-title":"Skin Microbiome Modulates the Effect of Ultraviolet Radiation on Cellular Response and Immune Function","volume":"15","author":"Patra","year":"2019","journal-title":"iScience"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/s0161-5890(01)00122-5","article-title":"T Cell Receptor Excision Circle Assessment of Thymopoiesis in Aging Mice","volume":"38","author":"Sempowski","year":"2002","journal-title":"Mol Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.870542\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T18:54:58Z","timestamp":1675709698000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.870542\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,30]]},"references-count":61,"alternative-id":["10.3389\/fimmu.2022.870542"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.870542","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,30]]},"article-number":"870542"}}